There is a great interest in synthetic methods directed toward the creation of large collections (libraries) of small organic compounds which could be screened for pharmacological activity. Often referred to as combinatorial chemistry, the synthetic methods applied to create vast combinatorial libraries are performed in solution or on the solid phase. Solid-phase synthesis makes it easier to conduct multistep reactions and to drive reactions to completion, because excess reagents can be added and easily washed away after each reaction step. Solid-phase combinatorial synthesis also makes isolation, purification or screening more manageable. However, more traditional solution phase chemistry supports a wider variety of organic reactions than the solid-phase. Typically, combinatorial methods involve selection of various structural components which are used to modify a core chemical structure. One adds individual structural components as part of a chemical synthesis sequentially, either in a controlled or random manner, to produce all or a substantial portion of the possible compounds that can result from the different choices possible at each sequential stage in the synthesis. Efficient use of this technique can create thousands of compounds for pharmacological screening in a short period of time.
Methods for screening libraries of compounds for binding properties to a receptor include methods wherein each member of the library is tagged with a unique identifier to facilitate identification of compounds having binding properties, and methods wherein the library comprises a plurality of compounds synthesized at particular locations on the surface of a solid substrate. The receptor may be appropriately labelled with a radioactive or fluorescent label that enables one to ascertain whether binding to the receptor of interest has occurred. Correlation of the labelled receptor bound to the substrate with its location on the substrate identifies the binding ligand as described in U.S. Pat. No. 5,143,854.
In contrast to the standard combinatorial chemistry approach which results in libraries with maximum diversity, there is a trend toward the design of more targeted libraries which minimize redundancy and improve screening efficiency.
One particular class of compounds that would be useful for inclusion in targeted libraries is quinazolinone compounds, including dihydro-quinazolinones and derivatives thereof. This class of compounds possesses a diverse array of pharmaceutical and chemical properties. For example, dihydro-quinazolinones are known to possess antipyretic, hypotensive, antibacterial, antifungal or Central Nervous System ("CNS") depressant activity as well as the ability to inhibit enzymes of biological importance, for example, metalloenzymes.
Bonola et al. (J. Med. Chem., 13, 329-332 (1970)) describe the synthesis of 2,3-dihydro-4(1H)-quinazolinone derivatives of the following formula: ##STR1##
where R is hydrogen, hydroxy, phenyl, substituted phenyl, and furyl and R.sup.1 is hydroxy, alkoxy, anilino, alkylamino, and alkyl (dialkylamino). These compounds are made by condensation of an appropriately substituted amine with isatoic anhydride. The corresponding aminobenzamide is then condensed with the appropriate aldehyde or ketone to yield a dihydro-quinazolinone. Alternatively, the condensation of 2-aminobenzohydroxamic acid with the appropriate aldehyde or ketone leads to the corresponding N-hydroxy-dihydroquinazolinone. Notably, all of the dihydroquinazolinones described above are prepared under neutral or basic conditions in alcoholic solvents or alcoholic solvents containing an alkoxide or amine base.
Christie et al. (J. Chem. Soc. Perkin Trans. I, 2779-2783 (1985)) describe the synthesis of dihydro-quinazolinones and N-hydroxy-quinazolinones by the reaction of the appropriate aminobenzamide or aminobenzohydroxamic acid with the appropriate corresponding aldehyde or ketone in an alcoholic solvent.
However, a simple procedure for synthesizing a multiplicity of quinazolinones on a variety of solid supports would create a combinatorial library, enhance the structural variation of the pharmacophore and provide the opportunity to evaluate the library through pharmacological screening to obtain important structure-activity information and potential drug candidates.
Accordingly, there is a clear need in the art for an efficient method for obtaining a library of 2,3-dihydro-quinazolinones, wherein the starting materials are amenable to large scale synthesis, and wherein the desired products can be obtained under relatively mild conditions employing readily available reagents.
Citation or identification of any reference in this section of this application shall not be construed as an admission that such reference is available as prior art to the present application.